Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy

Febrile seizures (FS) and temporal lobe epilepsy (TLE) were found in four of the seven siblings born to healthy Moroccan consanguineous parents. We hypothesized autosomal recessive (AR) inheritance. Combined linkage analysis and autozygosity mapping of a genome-wide single nucleotide polymorphism genotyping identified a unique identical by descent (IBD) locus of 9.6 Mb on human chromosome 8q12.1-q13.2. Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6). Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients. Structural modeling of CPA6 indicated that both mutations are located near the enzyme's active site. In contrast to wild-type CPA6, which is secreted and binds to the extracellular matrix where it is enzymatically active, Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix. This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.     

一个全面性癫痫伴热性惊厥附加症家系临床表型及GABRG2基因突变分析

目的 分析并确定一个全面性癫痫伴热性惊厥附加症(generalized epilepsy with febrile seizures plus,GEFS+)家系临床表型,并对其CABAA受体γ2哑单化基因(GABAA-receptor γ2 subunit,GABRG2)进行突变筛查及遗传特征分析.方法 收集先证者及其家系成员临床资料及外周血DNA,采用聚合酶链反应和DNA直接测序的方法进行GBRG2基因突变筛查,确定基因突变的位点,分析基因型与表型的关系.结果 该家系为典型GEFS+家系,3代共有7例受累成员,临床表型1例为热性惊厥(febrile seizures,FS),6例为热性惊厥附加症(febrile seizures plus,FS+).该家系先证者的GABRG2基因存在第9外显子的杂合无义突变c.1287G＞A(P.W390X),先证者之母和具有GEPS+表型的其他家系成员均携带该基因突变,1例携带该突变的家系成员临床表型正常,外显率约为87.5%(7/8).结论 该GEFS+家系GBRG2基因突变P.W390X为遗传性突变,家系符合常染色体显性遗传伴外显率小全.GABRG2基因突变也是中国GEFS+家系的致病基因之一.     

<Emphasis Type="Italic">SCN1A,</Emphasis><Emphasis Type="Italic">SCN1B</Emphasis>, and <Emphasis Type="Italic">GABRG2</Emphasis> gene mutation analysis in Chinese families with generalized epilepsy with febrile seizures plus

Generalized epilepsy with febrile seizures plus (GEFS+; MIM#604233) is a familial epilepsy syndrome characterized by phenotypic and genetic heterogeneity. It was associated with mutations in the neuronal voltage-gated sodium channel subunit gene (SCN1A, SCN2A, SCN1B) and ligand-gated gamma aminobutyric acid receptors genes (GABRG2, GABRD). We investigated the roles of SCN1A, SCN1B, and GABRG2 mutations in the etiology of Chinese GEFS+ families. Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood lymphocytes of 23 probands and their family members. The sequences of SCN1A, SCN1B, and GABRG2 genes were analyzed by polymerase chain reaction (PCR) and direct sequencing. The major phenotypes of affected members in the 23 GEFS+ families exhibited FS and FS+, whereas rare phenotypes afebrile generalized tonic-clonic seizures (AGTCS), myoclonic-astatic epilepsy (MAE), and partial seizures were also observed. A novel SCN1A mutation, p.N935H, was identified in one family and another novel mutation in GABRG2, p.W390X, in another family. However, no SCN1B mutation was identified. The combined frequency of SCN1A, SCN1B, and GABRG2 mutations was 8.7% (2/23), extending the distribution of SCN1A and GABRG2 mutations to Chinese GEFS+ families. There were still unidentified genes contributing to the pathogenesis of GEFS+.     

The NOD2 receptor does not play a major role in the pathogenesis of Group B Streptococcus in mice

Group B Streptococcus (GBS) capsular type III is an important agent of life-threatening invasive infections. It has been previously shown that encapsulated GBS is easily internalized by dendritic cells (DCs) and this internalization has an impact on cytokine production. The intracellular receptors or pathways underlying this response are not well understood. In this work, we investigated the role of NOD2 in the pathogenesis of GBS using a mouse model of infection. NOD2^−/− mice showed similar levels of survival and bacteremia than control mice. Interestingly, ex vivo analysis of total spleen cells from infected animals showed that the absence of NOD2 results in reduced production of inflammatory cytokines. However this abridged inflammatory response does not seem to improve mouse survival. In conclusion, we demonstrated that NOD2 is not a crucial receptor to fight GBS infection and only partially contributes to the inflammatory response.     

The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that approximately 4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1-5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane.